Alzheimer's disease (AD) is the most common form of dementia and is characterized by the progressive decline in cognitive function, with the primary deficits being hippocampal-mediated learning and memory loss. Recent studies suggest the involvement of glutamate in the pathology of the disease, as levels are decreased in the hippocampus of patients with AD. Glutamate modulates excitatory postsynaptic currents via (mGlus). The metabotropic glutamate receptor subtype 5 (mGlu5) is the most highly expressed in the hippocampus and is a close signaling partner of the NMDAR. The NMDA receptor is critical in regulating hippocampal synaptic plasticity and essential for hippocampal-dependent cognitive function. Therefore, increased activation of mGlu5 offers an exciting new therapeutic strategy to enhance cognitive function in patients suffering from AD. Recently, our group has developed a highly potent, selective series of mGlu5 positive allosteric modulators (PAMs) with enhanced physiochemical and pharmacokinetic properties for in vivo studies, providing an unprecedented opportunity to evaluate the potential of selective potentiation of mGlu5 as a novel target for the treatment of symptoms associated with AD. As opposed to direct activation of mGlu5, PAMs dramatically potentiate the response of the receptor to its endogenous ligand glutamate and offer high selectivity while avoiding unwanted side-effects seen with direct activation. Aged rats have a loss of hippocampal synaptic function as well as cognitive function and allow the opportunity to characterize the ability of our novel mGlu5 PAMs to restore these deficits in a preclinical animal model that best emulates the human disease state. Studies proposed will establish the ability of mGlu5 PAMs to restore deficits in synaptic function, determine the degree of in vivo occupancy of central mGlu5 necessary to observe in vivo efficacy using microPET and evaluate the cognitive-enhancing efficacy of mGlu5 PAMs in several preclinical models of cognitive function in aged rats.